Migraine, tension, and cluster headaches have distinct characteristics but share some common treatment approaches. Acute migraine is treated with analgesics, anti-inflammatories, vasoconstrictors, and serotonin agonists to control pain, nausea, and vascular changes. Prophylactically, medications aim to stabilize neuronal membranes, modulate serotonin levels, and affect neuroinflammation. Cluster headaches are treated acutely with oxygen and lidocaine and preventatively with verapamil, lithium, and prednisone.

1. Headache / Migraine
Hussein Hallak Ph.D.
Al-Quds University

2. Migraine Cluster Tension
Familial Yes No Yes
Sex Female Male Female
Onset Variable During Sleep Stress
Location Unilateral Behind Eyes Bilateral,
Around Head
Character Pulsating,
Throbbing
Excruciating,
Sharp, Steady
Dull, Persistent
Duration 2-72 hrs 15-19 min Up to 7 Days
Symptoms Visual Aura,
Sensitivity to
light and
sound, Pale
face, nausea,
vomiting
Sweating,
facial flushing,
nasal
congestion,
lacrimation
Mild tolerance
to light and
noise, anorexia

4. Cause of Migraine Headache:
Theories Not Facts
 Evidence strongly suggests that:
 Low levels of Serotonin are involved.
 Get vasodilation
 Release of vasoactive and inflammatory
peptides: substance P, neurokinin A, bradykinin,
from trigeminal fibers
 Cause inflammation  activation of nociceptive
pain

5. Treatment Strategies
 Acute management:
 Block vasodilation, release of inflammatory
mediators, and activation of trigeminal neurons,
you can abort the attack.
 Prophylactic agents:
 If you can figure out how to stop the generator
or abnormal activation of these systems, you
can prevent migraine attacks.

6. Migraine is a Progressive
Disease
Low Frequency
Episodic Migraine
Low Frequency
Episodic Migraine
1-2 days/month
Low Disability
Prevalence = 7.5%
Only requires acute
care
Most are treated with
OTCs
Intermediate Frequency
Episodic Migraine
Intermediate Frequency
Episodic Migraine
High Frequency
Episodic Migraine
High Frequency
Episodic Migraine
Chronic
Migraine
Chronic
Migraine
3-7 days/month
Some Disability
Prevalence = 2.5%
Some require prevention
(most use generic)
8-14 days/month
High Disability
Prevalence = 1.5%
All require prevention
and many failed to
generic
High Chance to
Develop Chronic
Migraine
15+ days/month
Highest Disability
Prevalence = 1.5%
All require prevention
Only BTX is FDA
approved
Relatively Stable, Low
Risk Pool
Episodic Migraine
Evolving to Chronic
Migraine
Most Refractory
Stage
Bigal M, Lipton RB, Headache 2006;46:245-252.
Bigal M,Lipton RB, Neurology. 2008 Sep 9;71(11):848-55.
Need Prevention
Primary Care
Neurologist/Headache Specialist

7. Acute Management -- Treat
Nausea and Vomiting
 Anti-emetic agents:
 Prochlorperazine
 Metoclopramide
 Chlorpromazine

8. Acute Management: Analgesics
 Aspirin, acetaminophen
 Non-steroidal anti-inflammatory agents
 Ibuprofen
 Naproxen sodium
 Indomethacin
 Ketorolac
 Inhibit cyclooxygenase activity, so decrease
prostaglandin formation
 Prostaglandins sensitize pain receptors
 Prostaglandins are involved in inflammation

9. FDA Approved Products
 Excedrine Migraine: Contains Acetaminophen,
Aspirin, and caffeine.
 Not clear what caffeine does, but National
Headache Foundation 1999 consensus is
that caffeine increases the effectiveness of
headache treatment by up to 40%.

10. Opioid Analgesics
 Not first line of defense for migraines.
 Guidelines (2000) -- used as “rescue”
medications when sedation is not an issue and
risk of abuse has been addressed.

11. Acute Management: 5-HT1B/D
Agonists: “Triptans”
Drugs:
 Sumatriptan (Imitrex)*
 Naratriptan (Amerge)*
 Zolmitriptan (Zomig)
 Rizatriptan (Maxalt)
 Almotriptan (Axert)
 Frovatriptan succinate (Frova)

12. Acute Management: 5-HT1B/D
Agonists
Pharmacology.
 Selective for 5-HT1B/D receptors. Little/no
affinity for other receptors.
 Constrict cerebral vasculature.
 Decrease release of inflammatory mediators
and neurally induced plasma extravasation.
 Inhibit activation of trigeminal neurons.

13. 5-HT1B/D Agonists, contíd
Pharmacokinetics.
 Use of triptans with longer half-lives may be
better, especially for patients with rebound
headaches (eg. Naratriptan (~6 hr),
Frovatriptan ~ 26 hr)).
 Metabolism of sumatriptan, zolmitriptan,
rizatriptan, and almotriptan all involve MAO.

14. 5-HT1B/D Agonists, Cont’d
Side effects
 Chest pressure / pain,
shortness of breath,
palpitations
 Paresthesias (tingling,
numbness, itching)
 Nausea / vomiting
 Dizziness
 Chronic daily headaches
with overuse
Contraindications
 Heart disease
 Peripheral vascular disease
 Uncontrolled hypertension
 Ergot alkaloids within the
past 24 hours
 MAO-inhibitors within past 2
weeks for sumatriptan,
zolmitriptan, rizatriptan,
almotriptan

15. Triptans Approved for Pediatrics
Almotriptan
 FDA-labeled for treatment of
acute migraine in adolescents
12-17 years old
 Randomized, double-blind,
placebo-controlled, parallel-
group trial in 12-17 year olds of
6.25 or 12.5 mg PO: pain relief
in 72-73% at 2 hours1
Rizatriptan
 FDA-labeled for treatment of
acute migraine in ages 6-17
 Labeled dosing: (MLT = Orally
Disintegrating Tablet)
 <40 kg: 5 mg MLT
 ≥40 kg: 10 mg MLT
 Randomized, double-blind,
placebo-controlled trial:
 73-74% had pain relief at 2
hours
 Second Trial: higher 2 hour
pain freedom rate in rizatriptan
vs. placebo.

16. Menstrual Migraines May Be Preventable:
Current Migraine Drugs Work for Headaches
With Monthly Periods
 Menstrual migraines, which are thought to be triggered by the
drop in estrogen levels, typically begin between two days
before and one day after the start of a woman's period.
 3 month study of frovatriptan (Frova), enrolling 545 women
who had suffered from menstrual migraine headaches for an
average of 12 years.
 Start two days before their period and continue for six days,
the patients were given either placebo, a 2.5, or 5 mg dose of
Frova.
 Headaches disappeared in half of patients treated with the
higher dose of Frova. In addition, headaches stopped in over
a third of patients taking the lower dose, compared with
about one-fourth taking placebo.

17. Acute Management: Ergot Alkaloids
 Ergotamine (Ergostat; Ergomar)
 Not used much anymore
 Dihydroergotamine (Injection D.H.E 45;
Nasal Spray (Migranal®)
 Used for Emergency Room / in-patient
management of intractable headache

18. Ergot Alkaloids, Cont’d
 Anti-migraine effect probably due to stimulation of
5-HT1B/1D receptors
 Also block re-uptake of norepinephrine
 Partial agonist / antagonist at other receptors
 Norepinephrine
 Serotonin
 Dopamine
 Other

19. Ergot Alkaloids, Cont’d
Side effects.
 nausea / vomiting.
 Contraindications -- due to vasoconstrictive and
oxytocic properties.
 Oxytocic: Agents promoting uterine contractions
 Drug interactions / precautions: profound
vasospasm.
 Macrolide antibiotics (eg. Erythromycin).
 Methysergide / other vasoconstrictors.

21. Prophylactic Management of Migraine
 Beta blockers -- Propranolol (Inderal), Nadolol.
 Not apparently due to beta receptor block.
 Contraindications as expected for beta blockers.
 Tricyclic antidepressants -- Amitriptyline (Elavil).
 Not FDA approved, but often used.
 Works well in patients with mixed muscle tension/migraine
headaches.
 Helps people sleep.
 Divalproex sodium (Depakote, Depakote-ER).
 Inhibits sustained, repetitive firing of neurons.

22. Preventive Treatment needs dose titration
 Topiramate dose titration phase for around 1 month
Titration
Week
1
Week
2
Week
3
AM
Dose
PM
Dose
Prescription
Week 4 and
beyond
+
25 25 25
25
25
25
50
50
 Medications need to be taken three times a day (propranolol), twice a
day (propranolol ER, topiramate) or once daily (TADs)

23. Prophylactic Management of Migraine
 Ca2+ channel blockers
 Verapamil
 Stabilizes neuronal membranes, decreases
neurotransmitter release
 SSRIs and “atypical anti-depressants”

24. FDA approved onabotulinum toxin A (Botox®) for the
prophylactic treatment of Chronic Migraine

27. Acute Treatment of Cluster Headache
 Lidocaine (Xylocaine)
 Local anesthetic. Given nasally provides
sphenopalatine ganglionic block
 Oxygen -- 100% for 15 min
 Triptans
 Effective in acute treatment of patients
with episodic cluster headache

28. When activated, the trigeminal nerve causes the eye pain
associated with cluster headaches. The trigeminal nerve also
stimulates another group of nerves that causes the eye tearing and
redness, nasal congestion and discharge associated with cluster
attacks

29. Prophylactic Treatment of Cluster
Headache
 Verapamil
 Methysergide
 Lithium (Eskalith, Cibalith)
 Affects phosphoinositide-based signaling
 May stabilize membranes
 Toxicity can be a concern
 Prednisone (Deltasone)
 Gabapentin (Neurontin)

30. Major Points to Know
 Vascular dilation and peri-vascular inflammation are
associated with acute migraine attacks
 Trigeminal system and serotonin implicated
 Acute management associated with controlling pain,
nausea, and vomiting
 Analgesics / anti-inflammatories
 Vasoconstrictors
 Serotonin 1B/D agonists
 Prophylactic management associated with stabilizing
membranes, modulating 5-HT levels, affecting
neuroinflammatory processes
 Treatment of cluster headache -- acute &
prophylactic